Role of HIV in acceleration of HPV malignancy

项目摘要/摘要 越来越多的证据表明，在艾滋病毒阳性的个人中，HPV相关肿瘤的发生率是 尽管进行了有效的抗逆转录病毒治疗，但感染率仍大大高于艾滋病毒阴性者。这些数据强烈地 提示HIV可能在HPV相关的肛门、宫颈和宫颈肿瘤的发生中起关键作用。 口咽腔。然而，人们对它实现这一目标的机制知之甚少。我们出版的 研究和初步数据表明，艾滋病毒可能与口腔和肛门上皮相互作用，产生组织 上皮细胞失去紧密和粘连连接的微环境。这些上皮细胞有多个 与上皮-间充质转化(EMT)一致的变化，这是一个多步骤的表观遗传过程 通过丧失细胞粘附力和增加上皮细胞的流动性。EMT在细胞分化过程中起重要作用 胚胎发生也在肿瘤的发展中起着关键作用。我们的数据显示口腔和肛门 从HIV感染者身上获得的粘膜上皮活检显示出典型的EMT迹象，即 黏附连接蛋白E-钙粘蛋白表达下调，波形蛋白表达上调。暴露于 非HIV感染者扁桃体上皮细胞与HIV Tat和gp120蛋白结合可诱导EMT。 此外，我们还观察到艾滋病毒感染与促炎细胞因子肿瘤的升高有关。 黏膜上皮细胞中的肿瘤坏死因子-α和干扰素-γ，也可能参与其中 在EMT的诱导过程中。已知HPV癌蛋白E6/E7可诱导EMT表型。因此， HIV和HPV可能通过几种途径与粘膜上皮细胞相互作用，并可能 协同建立EMT，从而加强HPV相关肿瘤的发生。一般而言，EMT 表型是可逆的，EMT细胞可能在EMT和正常状态之间来回转换，a 这一过程被称为间充质-上皮转化(MET)。MET的诱导或EMT的抑制可能 为预防和治疗HPV相关的口咽、颈部和肛门疾病提供了一种新的方法 这可能是降低HPV相关恶性肿瘤在HIV中的高发病率的一种新方法。 被感染的人。因此，我们的具体目标是：(1)研究HIV相关EMT的机制 在宫颈和肛门粘膜上皮细胞中的表达，并通过抑制波形蛋白和血管紧张素转换酶来诱导这些细胞中的MET 上调E-钙粘蛋白的表达，(2)探讨HIV和HPV在慢性粒细胞白血病发生发展中的协同作用 EMT表型，以及(3)研究抑制HIV和HPV诱导的EMT和激活EMT的作用 在减少HPV相关的宫颈和肛门细胞转化和侵袭方面。知识 通过这项工作产生的信息将对理解HIV和HPV 相互作用促进HPV相关的上皮性肿瘤的发展。这一知识也可能导致 可用于治疗HPV相关癌症和癌前病变的化合物的开发 通过抑制HIV/HPV诱导的EMT和激活MET来启动HIV感染。

Project summary/Abstract Accumulating evidence indicates that the incidence of HPV-associated neoplasia in HIV-positive individuals is substantially higher than in HIV-negative individuals despite effective antiretroviral therapy. These data strongly suggest that HIV may play a critical role in development of HPV-associated neoplasia of the anus, cervix and oropharyngeal cavity. However the mechanisms by which it does so are poorly understood. Our published work and preliminary data show that HIV may interact with oral and anal epithelia creating a tissue microenvironment where epithelial cells lose tight and adherence junctions. These epithelia have multiple changes consistent with epithelial-mesenchymal transition (EMT), a multistep epigenetic process characterized by loss of cell adhesion and increased mobility of epithelial cells. EMT is important in cell differentiation during embryogenesis but also plays a critical role in neoplastic progression. Our data show that oral and anal mucosal epithelial biopsies obtained from HIV-infected individuals show typical signs of EMT, i.e., the adherens junction protein E-cadherin is down-regulated and vimentin expression is up-regulated. Exposure of tonsil epithelial cells from HIV-uninfected individuals to HIV tat and gp120 proteins leads to induction of EMT. Additionally we observed that HIV infection is associated with elevation of proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) in mucosal epithelia, which may also be involved in induction of EMT. Finally, it is known that HPV oncoproteins E6/E7 can induce the EMT phenotype. Thus, there are several pathways through which HIV and HPV may interact with mucosal epithelia, and may synergize to establish EMT with consequent potentiation of HPV-associated neoplasia. In general the EMT phenotype is reversible and EMT cells may transition back and forth between EMT and the normal state, a process known as mesenchymal-epithelial transition (MET). Induction of MET or inhibition of EMT may represent a novel approach to prevention and treatment of HPV-associated oropharyngeal, cervical and anal neoplasia and may be a novel approach to reducing the high incidence of HPV-associated malignancy in HIV- infected individuals. Accordingly, our specific aims are: (1) To investigate mechanisms of HIV-associated EMT in cervical and anal mucosal epithelial cells and induction of MET in these cells by suppression of vimentin and upregulation of E-cadherin expression, (2) To investigate synergy between HIV and HPV in development of the EMT phenotype, and (3) To study the role of suppression of HIV- and HPV- induced EMT and activation of MET in the reduction of HPV-associated cervical and anal cell transformation and invasion. Knowledge generated through this work will be of great value to understanding the mechanisms by which HIV and HPV interact to potentiate development of HPV-associated epithelial neoplasia. This knowledge may also lead to development of compounds that may be useful for treatment of HPV-associated cancers and pre-cancers in the setting of HIV infection through inhibition of HIV/HPV-induced EMT and activation of MET.